1. Field of the Invention
The present invention relates to prodrugs of (N-alkylamino)alkoxybenzoylbenzofurans. More specifically, the invention relates to (N-alkyl-N-hydroxymethylamino)alkoxybenzoylbenzofurans and the phosphate esters thereof. It further relates to solutions, in particular parenteral solutions, of such prodrugs for use in the treatment of arrhythmia.
2. Description of the Related Art
2-n-Butyl-3-(3,5-diiodo-4-(.beta.-N-diethylaminoethoxy)benzoyl) benzofuran or 4-(2-(diethyl-amino)ethoxy)-3,5-diiodophenyl 2-butylbenzo[b]furan-3-yl ketone (hereinafter amiodarone) has been approved in an oral tablet form (CORDARONE.RTM.) for the treatment of life-threatening ventricular tachyarrhythmias in the United States since 1985. This drug is useful not only in treating these arrhythmias but also in treating less severe ventricular arrhythmias and many supraventricular arrhythmias including atrial fibrillation and reentrant tachyarrhythmias involving accessory pathways.
To treat arrhythmias, the compound may be administered in oral dosage forms such as in the form of a 200 mg tablet, or it may be administered in the form of an intravenous solution. See, for example, Escoubet, B. et al., "Suppression of Arrhythmias Within Hours After Single Oral Dose of Amiodarone and Relation to Plasma and Myocardial Concentrations", Am. J. Cardiol., (1985), 55:696-702, Mostow et al., "Rapid Suppression of Complex Ventricular Arrhythmias With High-Dose Oral Amiodarone", Circulation, (1986), 73:1231-8, Morady et al., "Intravenous Amiodarone in the Acute Treatment of Recurrent Symptomatic Ventricular Tachycardia", Am. J. Cardiol., (1983), 51:156-9 and Kadish et al. "The Use of Intravenous Amiodarone in the Acute Therapy of Life-Threatening Tachyarrhythmias", Progress in Cardiovascular Diseases, (1989), 31:4, 281-294.
Amiodarone is practically insoluble or slightly soluble in an aqueous solvent. Hence, it is difficult to formulate a dosage form suitable for intravenous administration. To aid the dissolution in water, for example, a surfactant has been suggested. Thus, the prior art intravenous dosage form for this compound, termed I.V. Cordarone, comprises amiodarone dissolved in a solvent comprising polysorbate 80 available under the tradename Tween-80, and benzyl alcohol. Prior art intravenous solutions of amiodarone will be designated IV Cordarone herein.
However, the use of this dosage form is highly undesirable because it exhibits deleterious cardiovascular effects attributable to the detergent. For example, Torres-Arrault et al. reported in Journal of Electrocardiology, 17 (2), 1984, pp 145-152, that Tween-80 is a potent cardiac depressant and causes hypotension in the dog. See also Gough et al., "Hypotensive Action of Commercial Intravenous Amiodarone and Polysorbate 80 in Dogs", Journal of Cardiovascular Pharmacology, (1982), 375-380. Further, Tween-80 is known to have anti-arrhythmic action. See Torres-Arrault, J. Electrocardiology, 17 (2), 1984, pp. 145-152, and Yasaka, et al., Cardiovascular Research 1979, 13: pp. 717-722.
Kosinzki, et al., Am. J. Cardiol., (1984) 4: 565-70, report that intravenous amiodarone (IV Cordarone) can result in significant impairment of left ventricular performance in patients with pre-existing left ventricular dysfunction. After acute intravenous bolus administration, patients with a left ventricular ejection fraction greater than 0.35 experienced improved cardiac performance due to both acute and chronic peripheral vasodilation. However, patients with a lower ejection fraction developed a 20% decrease in cardiac index and clinically significant elevation of right heart pressures after acute bolus administration.
Remme et al., Am. Heart J., (1991) 122: 96-103, report that intravenous amiodarone caused a 15% reduction in blood pressure and an 18% increase in heart rate, and a progressive reduction in contractility (V sub max) with a rise in left ventricular and diastolic pressure.
Bopp et al., J. Cardio. Pharmacol., (1985) 7: 286-289, report that IV Cordarone caused a decrease in the ejection fraction, an increase in pulmonary wedge pressure and a 15% decrease in dP/dt, and a 12% decrease in left ventricular work.
Each of the above three references discuss the effects of intravenous amiodarone (IV Cordarone), i.e., amiodarone solubilized for intravenous administration using polysorbate 80 and benzyl alcohol.
Both Tween 80 and benzyl alcohol have been required for dissolving amiodarone in prior art preparations. However, both Tween 80 and benzyl alcohol are known to cause hypotension, Munoz et al., European Heart Journal, (1988) 9: pp. 142-148; Varma, et al., Arzneim. Forsch (1985) 35(5), pp. 804-808. Also, the use of such prior art formulations in clinical studies has resulted in a clinically significant incidence of hypotension and resulting death. Scheinman, et al., Circulation (1995) 92: pp. 3264-3272; Levine et al. J. Am. Co. Cardiol. (1996) 27(1): 67-75; Mooss, et al., Am. J. Cardiol. (1990) 65: pp. 609-614; Kowey, et al., Circulation (1995) 92: pp. 3255-3263.
Further, Tween 80 is known to exert anti-arrhythmic action, as noted by Yasaka et. al., Cardiovascular Research (1979) 13: pp. 717-722.
U.S. Pat. No. 3,248,401, the disclosure of which is incorporated herein by reference in its entirety, issued Apr. 26, 1966 describes the preparation of 3-diethylaminoethoxybenzoyl benzofurans.
U.S. Pat. No. 5,234,949 discloses an amiodarone in acetate buffer formulation.
Physicians' Desk Reference, 1992, page 2446 under tradename Cordarone(r), provides the prescribing information relating to the oral form of this important product.
The Torres-Arrault, Taska and Gough articles described above set forth the hypotensive effects following intravenous administration of IV Cordarone (amiodarone in Tween-80).
The article "Intravenous Amiodarone", Clinical Progress in Electrophysiology and Pacing, (1986), 4:5, page 433, concludes that "Amiodarone, when administered intravenously, appears to have a rapid onset of action causing profound hemodynamic and electrophysiological effect."